Unsaturated heterocylic compounds find a wide variety of uses. For example, compounds of this class find uses as modulators of physiological processes that are mediated by ligand-activated receptors. Receptors that are activated by ligands are located throughout the nervous, cardiac, renal, digestive and bronchial systems, among others. In the nervous system, for example, heterocyclic compounds are capable of functioning as agonists or antagonists of receptors for neurotransmitters, neurohormones and neuromodulators. Ligand-activated receptors have been identified in a wide variety of species, including humans, other mammals and vertebrates as well as in invertebrate species. Therefore, compounds of this class are also able to modulate receptor-mediated processes throughout phylogeny and find uses in a wide variety of applications, e.g., as pharmaceuticals, insecticides, fungicides and other uses.
Receptors activated by excitatory amino acids, such as the amino acid L-glutamic acid (glutamate), are a major excitatory neurotransmitter receptor class in the mammalian central nervous system. Anatomical, biochemical and electrophysiological analyses suggest that glutamatergic systems are involved in a broad array of neuronal processes, including fast excitatory synaptic transmission, regulation of neurotransmitter release, long-term potentiation, long-term depression, learning and memory, developmental synaptic plasticity, hypoxic-ischemic damage and neuronal cell death, epileptiform seizures, visual processing, as well as the pathogenesis of several neurodegenerative disorders. See generally, Nakanishi et al., Brain Research Reviews 26:230-235 (1998); Monaghan et al., Ann. Rev. Pharmacol. Toxicol. 29:365-402 (1980). This extensive repertoire of functions, especially those related to learning, neurotoxicity, and neuropathology, has stimulated recent attempts to describe and define the mechanisms through which glutamate exerts its effects.
Glutamate has been observed to mediate its effects through receptors that have been categorized into two main groups: ionotropic and metabotropic. Ionotropic glutamate receptors are generally divided into two classes: the N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Both classes of receptors are linked to integral cation channels and share some amino acid sequence homology. GluR1-4 are termed AMPA (a-amino-3-hydroxy-5 methylisoxazole-4-propionic acid) receptors because AMPA preferentially activates receptors composed of these subunits, while GluRS-7 and KA1-2 are termed kainate receptors as these are preferentially sensitive to kainic acid. Thus, an “AMPA receptor” is a non-NMDA receptor that can be activated by AMPA. AMPA receptors include the GluR1-4 family, which form homo-oligomeric and hetero-oligomeric complexes which display different current-voltage relations and calcium permeability. Polypeptides encoded by GluR1-4 nucleic acid sequences can form functional ligand gated ion channels. An AMPA receptor includes a receptor having a GluR1, GluR2, GluR3 and/or GluR4 subunit. A NMDA receptor includes a receptor having NMDARI, NMDAR2a, NMDAR2b, NMDAR2c, NMDAR2d and/or NMDAR3 subunits.
Metabotropic glutamate receptors are divided into three groups based on amino acid sequence homology, transduction mechanism and pharmacological properties, namely Group I, Group II and Group III. Each Group of receptors contains one or more types of receptors. For example, Group I includes metabotropic glutamate receptors 1 and 5 (mGluR1 and mGluR5), Group II includes metabotropic glutamate receptors 2 and 3 (mGluR2 and mGluR3) and Group III includes metabotropic glutamate receptors 4, 6, 7 and 8 (mGluR4, mGluR6, mGluR7 and mGluR8). Several subtypes of a particular mGluR type may exist. For example, subtypes of mGluR1 include mGluR1a, mGluR1b, mGluR1c and mGluR1d.
Anatomical studies demonstrate a broad and selective distribution of metabotropic glutamate receptors in the mammalian nervous system. For example, mGluR1 is expressed in the cerebellum, olfactory bulb, hippocampus, lateral septum, thalamus, globus pallidus, entopeduncular nucleus, ventral pallidum and substantia nigra (Petralia et al., (1997) J. Chem. Neuroanat., 13:77-93; Shigemoto et al., (1992) J. Comp. Neurol., 322:121-135). In contrast, mGluR5 is weakly expressed in the cerebellum, while higher levels of expression are found in the striatum and cortex (Romano et al., (1995) J. Comp. Neurol., 355:455-469). In the hippocampus, mGluR5 appears widely distributed and is diffusely expressed.
Metabotropic glutamate receptors are typically characterized by seven putative transmembrane domains, preceded by a large putative extracellular amino-terminal domain and followed by a large putative intracellular carboxy-terminal domain. The receptors couple to G-proteins and activate certain second messengers depending on the receptor group. Thus, for example, Group I mGluR's activate phospholipase C. Activation of the receptors results in the hydrolysis of membrane phosphatidylinositol (4,5)-bisphosphate to diacylglycerol, which activates protein kinase C, and inositol trisphosphate, which in turn activates the inositol trisphosphate receptor to promote the release of 20 intracellular calcium.
A wide variety of heterocyclic compounds having activity as mGluR5 antagonists have been described in our International Publication No. WO 01/16121 and related national phase applications such as 09/387,073 (abandoned) and 10/217,800, issued as U.S. Pat. No. 6, 774,138, for modulating the activity of the mGluR5 receptor and for use in the treatment of mGluR5 mediated conditions. Because of the physiological and pathological significance of excitatory amino acid receptors generally, and metabotropic glutamate receptors in particular, there is a need to identify ever more effective methods of modulating excitatory amino acid receptor-mediated processes, as well as more effective therapeutic methods of treatment and methods for prevention of diseases. There is thus a continuing need in the art to identify new and increasingly potent members of a compound class that can modulate excitatory amino acid receptors.